Osteopontin (OPN) has been implicated in distant metastasis in breast cancer. Breast cancers with elevated OPN expression show increased metastases and plasma OPN levels are elevated in breast cancer patients with metastases. Breast cancer has a strong predilection for spreading to bone. OPN stimulates osteoclastic bone resorption which is an essential requisite for bone metastases. These results collectively suggest that OPN produced in breast cancer plays a stimulatory role in bone metastases. However, whether OPN contributes specifically to bone metastases or generally to all metastases is unclear. More importantly, the mechanism underlying OPN stimulation of metastases remains to be elucidated. In addition, determination of the regulatory mechanism of OPN production in breast cancer cells in bone is important for better understandings of the pathophysiology of bone metastases. Our hypothesis is "breast cancer-produced OPN promotes bone and non-bone metastases in autocrine/paracrine manner with increased production in bone". To perform the study, we have developed an orthotopic model of mouse breast cancer which produces large amounts of OPN and spreads to bone, lung and liver. Our Specific Aims are: 1.To examine the effects of over expression and inhibition of OPN on bone and non-bone metastases 2.To examine autocrine effects of OPN on breast cancer cells 3.To examine paracrine effects of OPN on osteoclastogenesis and angiogenesis 4.To determine the regulatory mechanism of OPN production in breast cancer cells in bone 5.To examine the effects of bisphosphonates on bone and non-bone metastases in relation to OPN production in breast cancer cells Bone metastasis is one of the major causes of increased morbidity and eventual mortality in breast cancer patients. Suppression of bone metastases is a major advancement in the management of breast cancer patients. This study will define the mechanism by which breast cancer-produced OPN contributes to thepathogenesis of bone and non-bone metastases. Moreover, the study will also clarify the molecular mechanism of the regulation of OPN production in breast cancer cells in bone. OPN is a potential therapeutic target for bone and also non-bone metastases in breast cancer.